The interaction of the T cell receptor (TCR) with its specific ligand, peptide-MHC, is only one com-ponent of the events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize cell surface antigens (co-receptors) and their soluble or cell associated ligands (counter-receptors) which play critical roles in cell-cell interaction and in the interaction of T cells with their environment. We have concentrated our efforts in a number of distinct areas: 1) We have shown that the interaction of the B7 family of antigens on antigen presenting cells (APC) with their co-receptors on T cells is critical for the activation of T cells and that this interaction can be mediated by expression of the B7 antigen on an APC separate from the APC presenting the nominal antigen ("trans costimulation"). The B7 family also was shown to play a critical role in the induction of CD40L, the counter-receptor for the B cell antigen CD40. The interaction of the CD40L with CD40 plays a critical role in T-B collaboration. 2) We have defined a new pathway of non-specific activation of T cells which is mediated by the Vitronectin Receptor (VNR), a member of the integrin superfamily. Ligation of the VNR on certain activated T cells could induce cytokine production by T cells that required expression of the zeta-chain, one of the components of the CD3 complex, but did not require occupancy of the TCR by its cognate antigen. The antigen-independent, TCR-dependent, VNR-mediated pathway may play an important role in chronic inflammation. The rapid induction of tyrosine phosphorylation of a 115 kD protein was shown to be one of the major effects of engagement of the VNR. 3) Continued studies of the role of the integrins in thymocyte development demonstrated that human CD4+CD8+ thymocytes could be divided into two major populations based on their differential capacity to adhere to fibronectin (FN). The FN- adherent population is less mature, expresses higher levels of CD4/CD8, and low levels of the TCR and CD69. In contrast, the non-adherent cells appear to have undergone positive selection and express lower levels of CD4 and/or CD8, high levels of the TCR, and high levels of CD69. It appears that the differentiation of the adherent population to the non- adherent is one of the critical steps of human thymocyte differentiation. Lastly, we have demonstrated that all human thymocyte subpopulations express two receptors (alpha3beta1 and alpha6beta1) for the extracellular matrix proteins, laminin and merosin. Furthermore, adhesion to these proteins can be induced by activation of the thymocytes and both laminin and merosin can costimulate thymocyte proliferation in the presence of suboptimal TCR stimulation.